Showing papers by "Edwin H. Cook published in 2012"
Harvard University1, Icahn School of Medicine at Mount Sinai2, Carnegie Mellon University3, Broad Institute4, Baylor College of Medicine5, University of Pennsylvania6, Brigham and Women's Hospital7, Vanderbilt University8, Johns Hopkins University9, French Institute of Health and Medical Research10, University of Texas Health Science Center at Houston11, University of Illinois at Chicago12, University of Pittsburgh13
TL;DR: Results from de novo events and a large parallel case–control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors and support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold.
Abstract: Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.
1,700 citations
Cornell University1, Nathan Kline Institute for Psychiatric Research2, New York University3, University of Michigan4, Emory University5, University of Pennsylvania6, University of Washington7, Columbia University8, Vanderbilt University9, Harvard University10, University of California, Los Angeles11, Montreal Children's Hospital12, University of Missouri13, Baylor College of Medicine14, University of Illinois at Chicago15, Cincinnati Children's Hospital Medical Center16, University of Minnesota17, Indiana University18
TL;DR: Clinical distinctions among categorical diagnostic subtypes of autism spectrum disorders were not reliable even across sites with well-documented fidelity using standardized diagnostic instruments, and results support the move from existing subgroupings of autism Spectrum disorders to dimensional descriptions of core features of social affect and fixated, repetitive behaviors.
Abstract: Context Best-estimate clinical diagnoses of specific autism spectrum disorders (autistic disorder, pervasive developmental disorder–not otherwise specified, and Asperger syndrome) have been used as the diagnostic gold standard, even when information from standardized instruments is available. Objective To determine whether the relationships between behavioral phenotypes and clinical diagnoses of different autism spectrum disorders vary across 12 university-based sites. Design Multisite observational study collecting clinical phenotype data (diagnostic, developmental, and demographic) for genetic research. Classification trees were used to identify characteristics that predicted diagnosis across and within sites. Setting Participants were recruited through 12 university-based autism service providers into a genetic study of autism. Participants A total of 2102 probands (1814 male probands) between 4 and 18 years of age (mean [SD] age, 8.93 [3.5] years) who met autism spectrum criteria on the Autism Diagnostic Interview–Revised and the Autism Diagnostic Observation Schedule and who had a clinical diagnosis of an autism spectrum disorder. Main Outcome Measure Best-estimate clinical diagnoses predicted by standardized scores from diagnostic, cognitive, and behavioral measures. Results Although distributions of scores on standardized measures were similar across sites, significant site differences emerged in best-estimate clinical diagnoses of specific autism spectrum disorders. Relationships between clinical diagnoses and standardized scores, particularly verbal IQ, language level, and core diagnostic features, varied across sites in weighting of information and cutoffs. Conclusions Clinical distinctions among categorical diagnostic subtypes of autism spectrum disorders were not reliable even across sites with well-documented fidelity using standardized diagnostic instruments. Results support the move from existing subgroupings of autism spectrum disorders to dimensional descriptions of core features of social affect and fixated, repetitive behaviors, together with characteristics such as language level and cognitive function.
437 citations
University of Pittsburgh1, Yale University2, University of Michigan3, University of California, Los Angeles4, Emory University5, Boston Children's Hospital6, Montreal Children's Hospital7, Icahn School of Medicine at Mount Sinai8, Geisinger Health System9, Cornell University10, Brown University11, Howard Hughes Medical Institute12, Vanderbilt University13, University of Illinois at Chicago14, Carnegie Mellon University15
TL;DR: It is shown that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk.
Abstract: Background: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods: By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results: By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions: Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.
381 citations
Trinity College, Dublin1, University of Pittsburgh2, Icahn School of Medicine at Mount Sinai3, University of Toronto4, University of Bologna5, Guy's and St Thomas' NHS Foundation Trust6, Goethe University Frankfurt7, King's College London8, Pasteur Institute9, University of Paris10, University College Dublin11, Instituto Gulbenkian de Ciência12, University of Lisbon13, University of Michigan14, Vanderbilt University15, Utrecht University16, University of Washington17, University of Oxford18, Memorial University of Newfoundland19, University of Miami20, McGill University21, University of Gothenburg22, University of Pennsylvania23, University of Manchester24, University of Illinois at Chicago25, Newcastle University26, Nathan Kline Institute for Psychiatric Research27, New York University28, University of Manitoba29, Cornell University30, Stanford University31, University of Toulouse32, Harvard University33, Indiana University34, National and Kapodistrian University of Athens35, Carnegie Mellon University36, Medical Research Council37, University of Iowa38, McMaster University39, Yale University40, University of Alberta41, University of British Columbia42, University of California, Los Angeles43, University of Utah44, University of North Carolina at Chapel Hill45, Autism Speaks46, Veterans Health Administration47, German Cancer Research Center48, Tufts University49, French Institute of Health and Medical Research50, Pierre-and-Marie-Curie University51, Centre national de la recherche scientifique52, Ohio State University53
TL;DR: Stage 2 of the Autism Genome Project genome-wide association study is reported, adding 1301 ASD families and bringing the total to 2705 families analysed, and it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
Abstract: While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
353 citations
University College Dublin1, Instituto Gulbenkian de Ciência2, Instituto Nacional de Saúde Dr. Ricardo Jorge3, Trinity College, Dublin4, Center for Autism and Related Disorders5, University of Bologna6, University of British Columbia7, Guy's Hospital8, Newcastle University9, King's College London10, University of Paris11, University of Illinois at Chicago12, University of Michigan13, University of Oxford14, Autism Speaks15, University of North Carolina at Chapel Hill16, Utrecht University17, Goethe University Frankfurt18, University of Washington19, Memorial University of Newfoundland20, University of Miami21, McGill University22, University of Gothenburg23, University of Pennsylvania24, Boston Children's Hospital25, German Cancer Research Center26, Icahn School of Medicine at Mount Sinai27, University of Manchester28, French Institute of Health and Medical Research29, New York University30, Nathan Kline Institute for Psychiatric Research31, Vanderbilt University32, University of Toulouse33, University of Toronto34, Indiana University35, University of Utah36, University of California, Los Angeles37, National and Kapodistrian University of Athens38, McMaster University39, Yale University40, University of Iowa41, University of Birmingham42, University of Alberta43, Stanford University44, Ohio State University45
TL;DR: A large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD highlights the applicability of HH mapping in complex disorders such as ASD and offers an alternative approach to the analysis of genome-wide association data.
Abstract: Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
182 citations
Baylor College of Medicine1, University of Amsterdam2, University of Lisbon3, Vanderbilt University4, University of California, Los Angeles5, University of Toronto6, French Institute of Health and Medical Research7, Icahn School of Medicine at Mount Sinai8, Wellcome Trust Sanger Institute9, Washington University in St. Louis10, McMaster University11, Memorial University of Newfoundland12, Yale University13, University of Illinois at Chicago14
TL;DR: The data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carn itine intake, loss, transport, or synthesis may beImportant in a larger fraction of nondys Morphic autism cases; and that the carnItine pathway may provide a novel target for therapy or prevention of autism.
Abstract: We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6-N-trimethyllysine) and decreased product levels (3-hydroxy-6-N-trimethyllysine and γ-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2–4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.
108 citations
TL;DR: The different spectrum and higher prevalence of developmental neuropathologic findings in the dup(15) cohort than in cases with idiopathic autism may contribute to the high risk of early onset of seizures and sudden death.
Abstract: The purpose of this study was to identify differences in patterns of developmental abnormalities between the brains of individuals with autism of unknown etiology and those of individuals with duplications of chromosome 15q11.2-q13 [dup(15)] and autism, and to identify alterations that may contribute to seizures and sudden death in the latter. Brains of 9 subjects with dup(15), 10 with idiopathic autism, and 7 controls were examined. In the dup(15) cohort, 7 subjects (78%) had autism, 7 (78%) had seizures, and 6 (67%) had experienced sudden unexplained death. Subjects with dup(15) autism were microcephalic, with mean brain weights 300 g less (1,177 g) than those of subjects with idiopathic autism (1,477 g; p < 0.001). Heterotopias in the alveus, CA4, and dentate gyrus and dysplasia in the dentate gyrus were detected in 89% of dup(15) autism cases but in only 10% idiopathic autism cases (p < 0.001). By contrast, cerebral cortex dysplasia was detected in 50% of subjects with idiopathic autism and in no dup(15) autism cases (p < 0.04). The different spectrum and higher prevalence of developmental neuropathological findings in the dup(15) cohort than in cases with idiopathic autism may contribute to the high risk of early onset of seizures and sudden death.
75 citations
TL;DR: Using neurochemical biomarkers to perform parallel studies in animal and human populations within a developmental context is a plausible approach to probe the root causes of ASD and to identify potential interventions.
Abstract: Objective Autism spectrum disorder (ASD) is a heritable but highly heterogeneous neuropsychiatric syndrome, which poses challenges for research relying solely on behavioral symptoms or diagnosis. Examining biomarkers may give us ways to identify individuals who demonstrate specific developmental trajectories and etiological factors related to ASD. Plasma oxytocin (OT) and whole-blood serotonin (5-HT) levels are consistently altered in some individuals with ASD. Reciprocal relationships have been described between brain oxytocin and serotonin systems during development. We therefore investigated the relationship between these peripheral biomarkers as well as their relationships with age. Method In our first study, we analyzed correlations between these two biomarkers in 31 children and adolescents who were diagnosed with autism and were not on medications. In our second study, we explored whether whole-blood 5-HT levels are altered in mice lacking the oxytocin receptor gene Oxtr . Results In humans, OT and 5-HT were negatively correlated with each other ( p Oxtr showed increased whole-blood 5-HT levels ( p = .05), with this effect driven exclusively by mice less than 4 months old ( p Conclusions Identifying relationships between identified ASD biomarkers may be a useful approach to connect otherwise disparate findings that span multiple systems in this heterogeneous disorder. Using neurochemical biomarkers to perform parallel studies in animal and human populations within a developmental context is a plausible approach to probe the root causes of ASD and to identify potential interventions.
70 citations
TL;DR: The higher prevalence of excessive A β accumulation in neurons in individuals with early onset of intractable seizures, and with a high risk of sudden unexpected death in epilepsy in autistic subjects with dup(15) compared to subjects with idiopathic ASD, supports the concept of mechanistic and functional links between autism, epilepsy and alterations of APP processing leading to neuronal and astrocytic Aβ accumulation and diffuse plaque formation.
Abstract: Background
It has been shown that amyloid s (Aβ), a product of proteolytic cleavage of the amyloid β precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type–specific amount
Methodology/Principal Findings
In the present study, we found that the percentage of amyloid-positive neurons increases in subjects diagnosed with idiopathic autism and subjects diagnosed with duplication 15q112-q13 (dup15) and autism spectrum disorder (ASD) In spite of interindividual differences within each examined group, levels of intraneuronal Aβ load were significantly greater in the dup(15) autism group than in either the control or the idiopathic autism group in 11 of 12 examined regions (p<00001 for all comparisons; Kruskall-Wallis test) In eight regions, intraneuronal Aβ load differed significantly between idiopathic autism and control groups (p<00001) The intraneuronal Aβ was mainly N-terminally truncated Increased intraneuronal accumulation of Aβ17–40/42 in children and adults suggests a life-long enhancement of APP processing with α-secretase in autistic subjects Aβ accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced α-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants Diffuse plaques containing Aβ1–40/42 detected in three subjects with ASD, 39 to 52 years of age, suggest that there is an age-associated risk of alterations of APP processing with an intraneuronal accumulation of a short form of Aβ and an extracellular deposition of full-length Aβ in nonfibrillar plaques
Conclusions/Significance
The higher prevalence of excessive Aβ accumulation in neurons in individuals with early onset of intractable seizures, and with a high risk of sudden unexpected death in epilepsy in autistic subjects with dup(15) compared to subjects with idiopathic ASD, supports the concept of mechanistic and functional links between autism, epilepsy and alterations of APP processing leading to neuronal and astrocytic Aβ accumulation and diffuse plaque formation
46 citations
TL;DR: This study identified a 1.3 kb deletion in A2BP1, which was subsequently validated by quantitative PCR and provided further support for the possible role of rare copy number variants in A 2BP1 in the development of autism and associated motor asymmetries.
Abstract: Ataxin 2 binding protein 1 (A2BP1 aka FOX1, RBFOX1) is an RNA binding protein responsible for regulation of pre-mRNA splicing events in a number of critical developmental genes expressed in muscle, heart and neuronal cells [Shibata et al. (2000); Mamm Genome 12:595-601; Jin et al. (2003); EMBO J 22:905-912; Underwood et al. (2005); Mol Cell Biol 25:10005-10016]. Rare copy number abnormalities of A2BP1 have been previously associated with cognitive impairment, attention deficit disorder and autism [Martin et al. (2007); Am J Med Gen Part B 144B:869-876; Elia et al. (2010); Mol Psychiatry 15:637-646.]. Using a 1M Illumina SNP microarray, we identified a 1.3 kb deletion in A2BP1, which was subsequently validated by quantitative PCR. Here we present an in depth case study of an individual with autism and mild developmental hemiparesis in whom the deletion was detected. This study provides further support for the possible role of rare copy number variants in A2BP1 in the development of autism and associated motor asymmetries.
38 citations
TL;DR: The results of this study represent the strongest linkage finding for OCD in a primary analysis to date and suggest that chromosome 1p36, and possibly several other genomic regions, may harbor susceptibility loci for OCD.
TL;DR: This study utilized publically available genome-wide association study data from the Autism Genome Project and annotated the results to generate an empirical P-value indicating statistically significant enrichment of expression quantitative trait loci in top results from the autism genome- wide association study.
Abstract: Autism spectrum disorder is a severe early onset neurodevelopmental disorder with high heritability but significant heterogeneity. Traditional genome-wide approaches to test for an association of common variants with autism susceptibility risk have met with limited success. However, novel methods to identify moderate risk alleles in attainable sample sizes are now gaining momentum. In this study, we utilized publically available genome-wide association study data from the Autism Genome Project and annotated the results (P <0.001) for expression quantitative trait loci present in the parietal lobe (GSE35977), cerebellum (GSE35974) and lymphoblastoid cell lines (GSE7761). We then performed a test of enrichment by comparing these results to simulated data conditioned on minor allele frequency to generate an empirical P-value indicating statistically significant enrichment of expression quantitative trait loci in top results from the autism genome-wide association study. Our findings show a global enrichment of brain expression quantitative trait loci, but not lymphoblastoid cell line expression quantitative trait loci, among top single nucleotide polymorphisms from an autism genome-wide association study. Additionally, the data implicates individual genes SLC25A12, PANX1 and PANX2 as well as pathways previously implicated in autism. These findings provide supportive rationale for the use of annotation-based approaches to genome-wide association studies.
TL;DR: The phenotypic model showed that prenatal smoking is not simply a marker of other maternal problem behaviors, and contributes to an emerging literature on sex-specific interaction effects for MAOA.
Abstract: This study illustrates the application of a latent modeling approach to genotype–phenotype relationships and gene × environment interactions, using a novel, multidimensional model of adult female problem behavior, including maternal prenatal smoking. The gene of interest is the monoamine oxidase A (MAOA) gene which has been well studied in relation to antisocial behavior. Participants were adult women (N = 192) who were sampled from a prospective pregnancy cohort of non-Hispanic, white individuals recruited from a neighborhood health clinic. Structural equation modeling was used to model a female problem behavior phenotype, which included conduct problems, substance use, impulsive-sensation seeking, interpersonal aggression, and prenatal smoking. All of the female problem behavior dimensions clustered together strongly, with the exception of prenatal smoking. A main effect of MAOA genotype and a MAOA × physical maltreatment interaction were detected with the Conduct Problems factor. Our phenotypic model showed that prenatal smoking is not simply a marker of other maternal problem behaviors. The risk variant in the MAOA main effect and interaction analyses was the high activity MAOA genotype, which is discrepant from consensus findings in male samples. This result contributes to an emerging literature on sex-specific interaction effects for MAOA.
Journal Article•